CYCLOBENZAPRINE HYDROCHLORIDE- cyclobenzaprine hydrochloride tablet, film coated
RedPharm Drug, Inc.
Cyclobenzaprine hydrochloride, USP is a white, crystalline tricyclic amine salt with the empirical formula C 20 H 21 N•HCl and a molecular weight of 311.9. It has a melting point of 217˚C, and a pK a of 8.47 at 25˚C. It is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. If aqueous solutions are made alkaline, the free base separates. Cyclobenzaprine HCl, USP is designated chemically as 3-( 5H –dibenzo[ a , d ]cyclohepten-5-ylidene)- N , N -dimethyl-1-propanamine hydrochloride, and has the following structural formula:
Cyclobenzaprine HCl USP, 10 mg is supplied as a 10 mg tablet for oral administration.
Cyclobenzaprine HCl tablets USP, 5 mg contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, magnesium stearate and opadry beige (hypromellose 6cP, titanium dioxide, PEG 400, iron oxide yellow and iron oxide red).
Cyclobenzaprine HCl tablets USP, 10 mg contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, magnesium stearate and opadry yellow (hypromellose 3cp, hypromellose 6cp, titanium dioxide, PEG 400, iron oxide yellow and polysorbate 80).
Cyclobenzaprine reduced or abolished skeletal muscle hyperactivity in several animal models. Animal studies indicate that cyclobenzaprine does not act at the neuromuscular junction or directly on skeletal muscle. Such studies show that cyclobenzaprine acts primarily within the central nervous system at brain stem as opposed to spinal cord levels, although its action on the latter may contribute to its overall skeletal muscle relaxant activity. Evidence suggests that the net effect of cyclobenzaprine is a reduction of tonic somatic motor activity, influencing both gamma (γ) and alpha (α) motor systems.
Pharmacological studies in animals showed a similarity between the effects of cyclobenzaprine and the structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Cyclobenzaprine caused slight to moderate increase in heart rate in animals.
Estimates of mean oral bioavailability of cyclobenzaprine range from 33% to 55%. Cyclobenzaprine exhibits linear pharmacokinetics over the dose range 2.5 mg to 10 mg, and is subject to enterohepatic circulation. It is highly bound to plasma proteins. Drug accumulates when dosed three times a day, reaching steady-state within 3-4 days at plasma concentrations about four-fold higher than after a single dose. At steady state in healthy subjects receiving 10 mg t.i.d. (n=18), peak plasma concentration was 25.9 ng/mL (range, 12.8-46.1 ng/mL), and area under the concentration-time (AUC) curve over an 8-hour dosing interval was 177 ng.hr/mL (range, 80-319 ng.hr/mL).
Cyclobenzaprine is extensively metabolized, and is excreted primarily as glucuronides via the kidney. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6, mediate N-demethylation, one of the oxidative pathways for cyclobenzaprine. Cyclobenzaprine is eliminated quite slowly, with an effective half-life of 18 hours (range 8-37 hours; n=18); plasma clearance is 0.7 L/min.
The plasma concentration of cyclobenzaprine is generally higher in the elderly and in patients with hepatic impairment.
In a pharmacokinetic study in elderly individuals (≥65yrs old), mean (n=10) steady-state cyclobenzaprine AUC values were approximately 1.7 fold (171.0 ng.hr/mL, range 96.1-255.3) higher than those seen in a group of eighteen younger adults (101.4 ng.hr/mL, range 36.1-182.9) from another study. Elderly male subjects had the highest observed mean increase, approximately 2.4 fold (198.3 ng.hr/mL, range 155.6-255.3 versus 83.2 ng.hr/mL, range 41.1-142.5 for younger males) while levels in elderly females were increased to a much lesser extent, approximately 1.2 fold (143.8 ng.hr/mL, range 96.1-196.3 versus 115.9 ng.hr/mL, range 36.1-182.9 for younger females).
In light of these findings, therapy with cyclobenzaprine HCl in the elderly should be initiated with a 5 mg dose and titrated slowly upward.
In a pharmacokinetic study of sixteen subjects with hepatic impairment (15 mild, 1 moderate per Child-Pugh score), both AUC and C max were approximately double the values seen in the healthy control group. Based on the findings, cyclobenzaprine HCl should be used with caution in subjects with mild hepatic impairment starting with the 5 mg dose and titrating slowly upward. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of cyclobenzaprine HCl in subjects with moderate to severe impairment is not recommended.
No significant effect on plasma levels or bioavailability of cyclobenzaprine HCl or aspirin was noted when single or multiple doses of the two drugs were administered concomitantly. Concomitant administration of cyclobenzaprine HCl and naproxen or diflunisal was well tolerated with no reported unexpected adverse effects. However combination therapy of cyclobenzaprine HCl with naproxen was associated with more side effects than therapy with naproxen alone, primarily in the form of drowsiness. No well-controlled studies have been performed to indicate that cyclobenzaprine HCl enhances the clinical effect of aspirin or other analgesics, or whether analgesics enhance the clinical effect of cyclobenzaprine HCl in acute musculoskeletal conditions.
Eight double-blind controlled clinical studies were performed in 642 patients comparing cyclobenzaprine HCl 10 mg, diazepam ** , and placebo. Muscle spasm, local pain and tenderness, limitation of motion, and restriction in activities of daily living were evaluated. In three of these studies there was a significantly greater improvement with cyclobenzaprine HCl than with diazepam, while in the other studies the improvement following both treatments was comparable.
Although the frequency and severity of adverse reactions observed in patients treated with cyclobenzaprine HCl were comparable to those observed in patients treated with diazepam, dry mouth was observed more frequently in patients treated with cyclobenzaprine HCl and dizziness more frequently in those treated with diazepam. The incidence of drowsiness, the most frequent adverse reaction, was similar with both drugs.
The efficacy of cyclobenzaprine HCl tablets, 5 mg was demonstrated in two seven-day, double-blind, controlled clinical trials enrolling 1405 patients. One study compared cyclobenzaprine HCl tablets, 5 mg and 10 mg t.i.d. to placebo; and a second study compared cyclobenzaprine HCl tablets, 5 mg and 2.5 mg t.i.d. to placebo. Primary endpoints for both trials were determined by patient-generated data and included global impression of change, medication helpfulness, and relief from starting backache. Each endpoint consisted of a score on a 5-point rating scale (from 0 or worst outcome to 4 or best outcome). Secondary endpoints included a physician’s evaluation of the presence and extent of palpable muscle spasm.
Comparisons of cyclobenzaprine HCl tablets, 5 mg and placebo groups in both trials established the statistically significant superiority of the 5 mg dose for all three primary endpoints at day 8 and, in the study comparing 5 and 10 mg, at day 3 or 4 as well. A similar effect was observed with cyclobenzaprine HCl tablets, 10 mg (all endpoints). Physician-assessed secondary endpoints also showed that cyclobenzaprine HCl tablets, 5 mg was associated with a greater reduction in palpable muscle spasm than placebo.
Analysis of the data from controlled studies shows that cyclobenzaprine HCl produces clinical improvement whether or not sedation occurs.
** VALIUM ® (diazepam, Roche)
A post-marketing surveillance program was carried out in 7607 patients with acute musculoskeletal disorders, and included 297 patients treated with cyclobenzaprine HCl tablets, 10 mg for 30 days or longer. The overall effectiveness of cyclobenzaprine HCl was similar to that observed in the double-blind controlled studies; the overall incidence of adverse effects was less (see ADVERSE REACTIONS).
Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, limitation of motion, and restriction in activities of daily living.
Cyclobenzaprine HCl should be used only for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use is not available and because muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration and specific therapy for longer periods is seldom warranted.
Cyclobenzaprine HCl has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease, or in children with cerebral palsy.
Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation. Hyperpyretic crisis seizures, and deaths have occurred in patients receiving cyclobenzaprine (or structurally similar tricyclic antidepressants) concomitantly with MAO inhibitor drugs.
Acute recovery phase of myocardial infarction, and patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure.
The development of a potentially life-threatening serotonin syndrome has been reported with
Cyclobenzaprine Hydrochloride when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. The concomitant use of cyclobenzaprine hydrochloride with MAO inhibitors is contraindicated (see CONTRAINDICATIONS). Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and /or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Treatment with Cyclobenzaprine Hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated. If concomitant treatment with Cyclobenzaprine Hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases(see PRECAUTIONS, Drug Interactions).
Cyclobenzaprine is closely related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. In short term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm, some of the more serious central nervous system reactions noted with the tricyclic antidepressants have occurred (see WARNINGS, below, and ADVERSE REACTIONS).
Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke.
Cyclobenzaprine HCl may enhance the effects of alcohol, barbiturates, and other CNS depressants.
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